Gastropresis is a symptomatic chronic disorder of the stomach characterized by delayed gastric emptying in the absence of mechanical obstruction. This condition is thought to affect up to 5 million individuals in the US. Standard medical therapy may involve dietary modifications, combining prokinetic and antiemetic agents, placing gastrostomy/jenunostomy tubes for enteral nutrition and implanting a gastric electrical stimulator. Current medical therapy of gastroparesis with prokinetic agents has been disappointing due to the limited options currently available. New concepts for diagnosis and treatment of gastroparesis are needed. Tegaserod (Zelnorm) is a selective partial 5-HT4 receptor agonist with prokinetic effects, derived from a new chemical class, the aminoguanidine indoles. Tegaserod in doses of 18 and 24 mg/day was reported to accelerate gastric emptying in patients with delayed gastric emptying. There are no clinical trials reporting symptom responses. Based on the data generated in multicenter studies, the United States Food and Drug Administration approved gastric electrical stimulation (GES) (ENTERRA Therapy System, Medtronic, Minneapolis, MN) in March 2000 under a Humanitarian Device Exemption for symptomatic relief in patients with diabetic and idiopathic gastroparesis. While some results obtained so far are encouraging, a number of important issues remain to be clarified including its efficacy in rigorous double-blind trial design, which stimulation parameters are optimal, long-term efficacy and safety follow-up, predictors of success in diabetic and idiopathic etiologies, and mechanisms of action. This proposal addresses three goals: Aim 1: To determine the efficacy and tolerability of tegaserod using a dose-titration approach and double blind withdrawal design with the primary endpoint reflecting improvement in upper Gl symptoms and quality of life in gastroparetic patients (short-term study). Measurements of gastric myoelectrical activity, gastric emptying, gastric tone and accomodation visceral sensitivity will also be performed to test the hypothesis that tegaserod can improve both subjective and objective aspects of gastroparesis. Aim 2: To investigate short and long-term efficacy, safety and mechanisms of action of high-frequency GES in gastroparetic patients (long-term study). We will initially conduct a double-blind crossover design trial and then long-term follow-up to achieve these goals. Electrogastrogram, barostat, positron emission tomography (PET) imaging, gastric emptying test, GE reflux testing and hormonal assays will be integrated. We hypothesize that high-frequency GES therapy will safely achieve and sustain a significant improvement in Gl symptoms, quality of life of patients but treatment failures need to be identified and profiled. Aim 3: To establish a large database to provide information on demographics, symptoms and quality of life status, etiologies, diagnostic testing data, therapies and outcomes of gastroparetic patients.